Establishing how deficient PKA-I activity results in abnormal T cell effector functions is a key step in understanding the etiopathogenesis of T cell dysfunction in SLE. In T cells from normal subjects, IL-2 induced IL-13+ cell accumulation in vitro is inhibited by the strong PKA activator PGE2, whereas the weak PKA activator beta-agonist causes increased accumulation. In SLE subjects with a severe defect in PKA activity, both PGE2 and ISO cause a profound increase in IL-2 induced IL-13+ cell accumulation. This R21 application proposes to clarify the effect of defective PKA on regulatory features of T cell accumulation in SLE subjects. The hypothesis is that the subpopulation of SLE subjects with defects in PKA activity has exaggerated accumulation of type 2 cells when stimulated by beta-agonist and PGE2. Further hypothesis is that experimental knockdown/expression of the PKA RI[unreadable]-subunit is sufficient to cause/reverse this effect. These hypotheses will be tested using a highly interpretive in vitro model and a well characterized cohort of SLE subjects. Results from these studies will provide novel insight into the regulation of T cell development of interest to the basic science of T cell biology, and advance our understanding of immune system regulation in SLE.